The AMP-activated protein kinase (AMPK) acts as an intracellular metabolic sensor in a variety of cells, where it monitors and responds to variations in the AMP:ATP ratio (Hardie et al., Annu. Rev. Biochem. 67:821-855, 1998). Upon activation of AMPK, the enzyme phosphorylates a number of protein substrates to decrease further ATP usage by the cell. AMPK is a heterotrimeric complex consisting of a catalytic subunit (α) and two associated subunits (β and γ). Both the β and γ subunits are required for optimal activity of the α catalytic subunit. The AMPK complex is evolutionarily conserved and also can be found in yeast and plants. Mammalian AMPK is composed of different isoforms of subunits: α1, α2, β1, β2, γ1, γ2, and γ3 (Hardie and Hawley, BioEssays 23:1112-1119, 2001). Different combinations of isoform subunits are activated differently in vivo, and most likely also differ in substrate utilization. AMPK activity is found in several tissues, including liver, kidney, muscle, lung, and brain (Cheung et al., Biochem. J. 346:659-669, 2000).
AMPK is recognized as a major regulator of lipid biosynthetic pathways due to its role in the phosphorylation and inactivation of key enzymes such as acetyl-CoA carboxylase (Hardie and Carling, Eur. J. Biochem. 246:259-273, 1997). More recent work has suggested that AMPK has a wider role in metabolic regulation (Winder and Hardie, Am. J. Physiol. 277:E1-E10, 1999); this includes fatty acid oxidation, muscle glucose uptake, expression of cAMP-stimulated gluconeogenic genes such as PEPCK and G6Pase, and expression of glucose-stimulated genes associated with hepatic lipogenesis, including fatty acid synthase, Spot-14, and L-type pyruvate kinase. Chronic activation of AMPK also can induce the expression of muscle hexokinase and glucose transporters (Glut4), mimicking the effects of extensive exercise training (Holmes et al. J. Appl. Physiol. 87:1990-1995, 1999). The activation of AMPK thus might be a good approach to treat type 2 diabetes; this hypothesis is supported by the finding that AMPK is the target for metformin, a drug widely used to treat type 2 diabetes (Zhou et al. J. Clin. Invest. 108:1167-1174, 2001).